The present invention relates to novel compounds for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain cis-.DELTA..sup.4 analogs of D and F series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage, and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not filly understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure ("IOP") can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the flow of aqueous humor out of the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects, such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Beta-blockers have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics may cause tachycardia, arrhythmia and hypertension. Recently, certain prostaglandins and prostaglandin derivatives have been described in the art as being useful in reducing intraocular pressure. Typically, however, prostaglandin therapy for the treatment of elevated intraocular pressure is attended by undesirable side-effects, such as irritation and hyperemia of varying severity and duration. There is therefore a continuing need for therapies which control elevated intraocular pressure associated with glaucoma without the degree of undesirable side-effects attendant to most conventional therapies.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G.sub.2, which is subsequently converted to prostaglandin H.sub.2. Other naturally occurring prostaglandins are derivatives of prostaglandin H.sub.2. A number of different types of prostaglandins have been discovered including A, B, D, E, F, G, I and J-Series prostaglandins (EP 0 561 073 A1). Of interest in the present invention are compounds which are believed to exhibit IOP lowering mechanisms similar to those exhibited by PGD.sub.2 (a D-series prostaglandin of formula I) and PGF.sub.2.alpha. (an F-series prostaglandin of formula II): ##STR1##
The relationship between PGD.sub.2 receptor activation and IOP lowering effects is not well understood. Various publications have reported that PGD.sub.2 receptor activation leads to second messenger activation and in particular, to the stimulation of adenylate cyclase and resultant increases in cAMP levels (Thierauch, Prostaglandins and their Receptors: II. Receptor Structure and Signal Transduction, Journal of Hypertension, volume 12, pages 1-5 (1994). Regardless of the mechanism, PGD.sub.2 has been shown to lower IOP (Nakajima, Effects of Prostaglandin D.sub.2 and its analogue, BW245C, on Intraocular Pressure in Humans, Graefe's Archive Ophthalmology, volume 229, pages 411-413 (1991)). Thus, it has been of interest in the ophthalmic field to develop synthetic PGD.sub.2 analogs with IOP lowering efficacy.
Synthetic PGD.sub.2 -type analogs have been pursued in the art (Graefe's Archive Ophthalmology, volume 229, pages 411-413 (1991)). Though PGD.sub.2 -type molecules lower IOP, these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects have included an initial increase in IOP, conjuctival hyperemia, increases in microvascular permeability, and increases in eosinophile infiltration (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, volume 4, No. 11, pages 44-50 (1993)).
Similarly, the relationship of PGF.sub.2.alpha.. receptor activation and IOP lowering effects is not well understood. It is believed that PGF.sub.2.alpha., receptor activation leads to increased outflow of aqueous humor. Regardless of the mechanism, PGF.sub.2.alpha. and certain of its analogs have been shown to lower IOP (Giuffre, The Effects of Prostaglandin F.sub.2.alpha., the Human Eye, Graefe's Archive Ophthalmology, volume 222, pages 139-141 (1985); and Kerstetter et al., Prostaglandin F.sub.2.alpha. -1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, volume 105, pages 30-34 (1988)). Thus, it has been of interest in the field to develop synthetic PGF.sub.2.alpha., analogs with IOP lowering efficacy.
Synthetic PGF.sub.2.alpha. -type analogs have been pursued in the art (Graefe's Archive Ophthalmology, volume 229, pages 411-413 (1991)). Though PGF.sub.2.alpha. -type molecules lower IOP, a number of these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology volume 4, No. 11, pages 44-50 (1993)).
Based on the foregoing, a need exists for the development of molecules that may activate the PGD.sub.2 and/or PGF.sub.2.alpha. receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits the same or improved efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a class of IOP lowering agents with an improved therapeutic profile over their PGF.sub.2.alpha. and PGD.sub.2 counterparts, and methods of their use. It has now unexpectedly been discovered that the presently claimed cis-.DELTA..sup.4 analogs of PGF.sub.2.alpha. and PGD.sub.2 meet this objective. Certain cis-.DELTA..sup.4 analogs of PGF.sub.2.alpha. (Nedy and Johnson, J. Org. Chem., 45:6, 1121 (1980); Bowler et. al. Prostaglandins, 17:6, 789 (1979); DE 2,716,972; DE 2,637,384; DE 2,623,139; U.S. Pat. No. 3,954,835) and PGD.sub.2 (EPO 299,914 B1) are known in the art. The metabolic profiles of cis-.DELTA..sup.4 PGF.sub.2.alpha. and (15S)-15-methyl-cis-.DELTA..sup.4 PGF.sub.2.alpha. relative to the corresponding cis-.DELTA..sup.5 isomers have also been discussed in the art (Green et. al, Eur. J. Biochem., 62, 527 (1976); Green, Prostaglandins, 15:5, 813 (1978); Hansson, Prostaglandins, 18:5, 745 (1979); Tarpley and Sun, J. Med. Chem., 21:3, 288 (1978)). However, the surprisingly enhanced therapeutic profiles of such compounds and the novel compounds of the present invention in the treatment of glaucoma are neither disclosed nor suggested in that art.